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Metabolism and the Other Fat:
A Protocadherin in Mitochondria
Nicholas E. Baker1,2,3,* and Andreas Jenny1,2,*
1Department
of Genetics
of Developmental and Molecular Biology
3Department of Ophtalmology and Visual Sciences
Albert Einstein College of Medicine, Bronx, NY, USA
*Correspondence: nicholas.baker@einstein.yu.edu (N.E.B.), andreas.jenny@einstein.yu.edu (A.J.)
http://dx.doi.org/10.1016/j.cell.2014.08.039
2Department
The protocadherin Fat is known as a tumor suppressor regulating growth in Drosophila and for its
conserved function during planar cell polarity establishment. McNeill and colleagues now identify
an unsuspected role for a C-terminal proteolytic product of Fat in mitochondria: regulating the electron transport machinery and metabolism.
In a surprising new paper in this issue of
Cell, Sing et al. (2014) report that the mitochondrial electron transport chain depends directly on a polypeptide imported
into the mitochondrion after cleavage
from a large transmembrane receptor at
the cell surface, Fat (Ft). This FtMito species helps to assemble or maintain complexes I and V, required for oxidative
phosphorylation and ATP generation.
This is all the more remarkable because
Ft was hardly an unstudied protein but
for some years has been the focus of
intense attention for its roles in growth
control, tumor suppression, and planar
cell polarity (PCP) (Figure 1; Thomas and
Strutt, 2012; Sharma and McNeill, 2013).
This provocative new study suggests
that these processes may be coupled to
mitochondrial function and signaling and
raises numerous questions about the
function and regulation of mitochondria.
The protocadherin Ft together with
the ligand Dachsous (Ds) forms one of the
two systems that establish PCP, the asymmetry of cells within the plane of the epithelium, and thus controls the formation of
asymmetric structures and morphogenetic
cell behaviors, a function likely conserved
between Drosophila and vertebrates
(Figure 1; Sharma and McNeill, 2013). Ft
also regulates growth through the
conserved Salvador-Warts-Hippo (SWH)
pathway of tumor suppressors by inhibiting
the transcription factor Yorki (the homolog
of mammalian Yap and Taz). Neither the
molecular mechanism connecting Ft to
the SWH pathway nor its conservation are
yet fully elucidated (Bossuyt et al., 2014).
Sing et al. started by characterizing
potential Ft-binding proteins recovered
from a two-hybrid screen, using RNAi
experiments in vivo. Surprisingly, three
interactors showing PCP phenotypes
were mitochondrial proteins: NADH dehydrogenase ubiquinone flavoprotein 2
(Ndufv2), mitochondrial processing protease (Mpp), and the V-ATPase component CG1746. Subsequent studies
showed that, like ft mutants, Ndufv2
knockdown impairs SWH signaling.
Remarkably, a fraction of both transfected and endogenous Ft colocalized
with the mitochondrial marker CVa and
Ndufv2 in cultured cells. Cell fractionation revealed that mitochondrial Ft corresponds to a 68 kDa cleavage product
(FtMito), derived from the Ft intracellular
domain and residing inside of mitochondria. FtMito may be produced by a cleavage occurring at the cell surface, as it is
not produced unless the Ft intracellular
domain is expressed with its transmembrane segment.
Sing et al. then made use of the characteristic large mitochondria found in developing sperm and saw that mitochondria
from ft mutant cells are swollen and
rounded and lack proper christae morphology. These cell-autonomous structural defects are accompanied by functional deficiencies assayed in imaginal
disc tissues, where superoxide levels
and markers of oxidative stress were
elevated by mutation of ft, as were cellular
lactate levels, indicating a higher level of
glycolysis accompanying the reduction
in mitochondrial complex I activity.
1240 Cell 158, September 11, 2014 ª2014 Elsevier Inc.
The ft mutant phenotype is comparable
to that caused by loss of a known complex I assembly factor. Intriguingly, FtMito
is detected in intact complex I. Although
levels of individual complex I proteins
are not affected in ft mutants, levels of
the intact complex are reduced significantly. Levels of complex V are diminished also, although FtMito itself is not
detected in complex V.
The authors hypothesize that Ft connects growth with metabolism: cleavage
of the FtMito fragment, which may prevent
Ft from inhibiting growth through the SWH
pathway, enhances assembly of complex I and complex V, thereby enhancing
oxidative phosphorylation at the expense
of glycolysis. What would be the purpose
of such a shift? Although ATP might be
required to support the growth that
should accompany reduced SWH signaling, the authors did not see much effect
of ft mutations on ATP levels, which may
be partially compensated by increased
glycolysis. In addition, it is generally
thought that glycolysis rather than oxidative phosphorylation is the favored energy
source for growing cells, as glycolysis,
accompanied by citrate export from mitochondria, provides building blocks for
biosynthesis of nucleotides, amino acids,
and lipids, in contrast to oxidative phosphorylation, which burns carbon through
the TCA cycle (Vander Heiden et al.,
2009). The authors expect, therefore,
that processing of Ft for mitochondrial entry may mitigate the enhanced growth signals expected as a result of diminished tumor suppression with a switch away from
Figure 1. The Diverse Functions of Fat
The protocadherin Fat (top) has long been known to regulate the establishment of planar cell polarity. For example, the planar polarity of cells in the Drosophila eye
is reflected in the asymmetry of ommatidial clusters; the distribution of two chiral forms is summarized on the left. Fat also acts as tumor suppressor repressing
growth (the wild-type eye-antennal imaginal disc (right) is smaller than the ft mutant). Sing et al. now have identified a novel role for a C-terminal proteolytic
fragment of Fat in oxidative phosphorylation in mitochondria (center). The possible interplay between the different functions awaits further elucidation, as discussed in the text. Eye disk images have been adapted from Zhao et al. (2013).
glycolysis toward oxidative phosphorylation. This is to be contrasted with the
effects of ft mutations, wherein growth
promotion would be accompanied by
enhanced dependence on glycolysis.
Many human tumors have mutations in
Fat homologs (Morris et al., 2013).
These findings raise a multitude of
questions. What, for example, is the
stoichiometry of Ft processing? Is sufficient FtMito produced to significantly
affect the capacity for SWH and PCP
signaling? Is FtMito a constituent of the
complex I, and does every complex I
contain Ft polypeptides? Because complex I assembly is not completely lost in
ft mutants and Ft has not been identified
in proteomic studies of mitochondria
(Pagliarini et al., 2008), it is also possible
that FtMito is a regulator or assembly factor. Does the location of full-length Ft on
the cell surface and its believed role as a
cell surface receptor in PCP and in growth
control imply that mitochondria are regulated by extracellular cues through Ft?
Curiously, mutants for Ft’s extracellular
ligand Dachsous do not show a parallel
reduction in complex I assembly, leaving
this question open. Last but not least,
what regulates mitochondria in nonepithelial tissues or in organisms that lack
Ft proteins, such as C. elegans or
S. cerevisiae?
Do these roles of Ft imply functional
connections between mitochondrial function, SWH tumor suppressor signaling,
and PCP (Figure 1)? The molecular mechanism connecting Ft to the SWH pathway
has been far from clear, raising the possibility that Ft signaling to SWH is indirect
and is mediated by mitochondria. It is
intriguing that knockdown of other mitochondrial components leads to PCP defects and changes in SWH activity, which
could indicate roles for mitochondria in
PCP and growth control, and that there
appears to be a gradient of ROS levels
within the developing eye that resembles
the gradient of Ft activity responsible for
PCP. For the time being, however, Sing
et al. take the conservative view that
mitochondrial stability, PCP, and tumor
suppression may be largely separable,
chiefly because conserved Ndufv2-binding sequences within the Ft intracellular
domain are required for its mitochondrial
function, but not for growth suppression
through the SWH pathway and for PCP.
In their view, some of the unexplained
effects of mitochondria on PCP and
SWH signaling may reflect feedback
pathways. These data, like previous
structure-function analyses of Ft, are not
clear-cut, however, so the last chapter
may not have been written on this interesting topic.
ACKNOWLEDGMENTS
The authors thank H. McNeill for discussions and
M. A. Simon for a figure panel. Research on growth
and PCP in the authors’ labs is supported by
grants from the NIH (GM088202 to A.J. and
GM104213 to N.E.B.) and American Heart Association (13GRNT14680002 to A.J.) and by an Unrestricted Grant from Research to Prevent Blindness
to the Department of Ophthalmology and Visual
Sciences (N.E.B.).
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